MacArthur “Genius” Grant Winner Battles Drug-Resistant Infections

In Earth’s earliest days tiny microbial reactions helped shape our planet’s evolution and composition. Certain ancient organisms managed to thrive even before the planet had readily accessible oxygen in the atmosphere, thanks to their ability to tap other substances like arsenic or iron for the electron-transfer reactions crucial for metabolism. Dianne Newman is best known for her work exploring how these ancient microbes obtained their nutrients, and how their metabolic reactions shaped the geochemistry of their environments. She revealed the cellular machinery behind these processes, and started a new field called molecular geomicrobiology.

But in recent years Newman, a Howard Hughes Medical Institute investigator and professor of biology and geobiology at the California Institute of Technology, has built off of her geologic studies of the distant past to tackle one of humanity’s most pressing current problems: She is applying her knowledge of these microbial communities to medicine, studying pathogens responsible for chronic infections in the human body. She hopes to use this to find ways to attack certain drug-resistant microbes.

Earlier this year Newman scooped up a National Academy of Sciences Award in Molecular Biology for her “discovery of microbial mechanisms underlying geologic processes.” Thursday she netted another prestigious award—a MacArthur Foundation fellowship grant, which is an annual accolade often nicknamed a “genius” award. This year’s 23 award winners each receive $625,000, paid out over five years.

Other scientists included in this year’s list of winners include Rice University’s Rebecca Richards-Kortum, a bioengineer who develops point-of-care diagnostic technologies; Victoria Orphan, a California Institute of Technology professor of environmental science and geobiology; Manu Prakash, a Stanford University bioengineer whose accomplishments include building a cheap, foldable microscope; and Bill Thies, a researcher at Microsoft who focuses on building communication technologies to help low-income communities.

Scientific American spoke with Newman about her plans for the award money, the importance of speaking up for the “little guy”—meaning her beloved bacteria—and why her leap into medicine is not that surprising.

[An edited transcript of the interview follows.]

I love to give readers insights into researchers’ lives or even their offices. Is there anything interesting in your office or on your desk you could tell me about?
Outside of my office is a floor that has gigantic laminate shapes of bacteria. These are really huge, colorful bacteria that are the organisms that we have worked on over the years.

Do you think of those pictures the way some people do their kids’ pictures?
Oh definitely. I am proud to be a pied piper of the microbes and I have this celebratory thing outside my door that showcases their glory. Every microbiologist in the field has affection for the organisms they study, and this moral obligation to speak up for the little guys—literally—because they are tiny but they have such an outsize influence on the world and have had that for billions of years of history.

You are best known for your work on how certain microbes can survive in low-oxygen environments, but you recently discovered what it takes for a multidrug-resistant pathogen called Pseudomnas aeruginosa to survive in patients with cystic fibrosis. Can you talk about that?
It’s actually not as big a leap as you might imagine. Conceptually you could replace an iron mineral surface with a surface like an infected lung in the context of cystic fibrosis, where you have mucus collecting on lung epithelial cells. It’s the same problem at a very basic level: How do bacteria survive when they are limited for oxygen or an iron oxide mineral or anything else that could be an oxidant—something that can be used by cells at the end of the electron transport chain in respiration to pick up electrons and make the whole process go—to power metabolism? How do they cope? It’s a neat problem.

You have published about how phenazines are the electron-shuttling compounds utilized by this pathogen, P. aeruginosa.How will this knowledge help you attack this infection (which is currently treated—with mixed success—with antibiotics)?
The reason we think that phenazines are relevant to cystic fibrosis, and possibly other infections, is that we find them in high concentrations in the sputum of people with cystic fibrosis as infections progress. We have a lot of data linking phenazine concentration to decline in lung function. We know how this one pathogen utilizes phenazines, so we’re thinking about how to inhibit that—to block phenazine cycling so it can’t be used as an electron shuttle.

So are you making any progress on that?
This is our current work right now and it’s getting exciting. One of the best ways to do this is look to nature for solutions. A fascinating thing about P. aeruginosa is it’s a pretty cosmopolitan organism—you find it in gardens and in soil, and it’s probably been there for millions of years. For however long it’s been making phenazines you can bet organisms co-evolved with it, and figured out ways to deal with these phenazines. One way to deal with them is to eat them and break them down—to degrade them. So we isolated a different soil organism that could do this, and we are currently working out the biochemistry of the enzymes that it uses to break phenazines down, and we are exploring how we could leverage that to control the pathogen.

Assuming these enzymes turn out to be are safe for human use, the idea is that you would treat patients with them to vanquish these bacterial communities?
Yes, that’s the dream scenario—the pie-in-the-sky dream. We are in the beginning of this project though, and we don’t know if this is going to work—and there are lots of reasons this might fail. We do have reason to think there are other infections where phenazines matter, too, so this could have other applications as well. There are chronic wounds where P. aeruginosa is important: diabetes foot wounds, burn victim wounds and people with AIDS can get chronic infection with P. aeruginosa as a hospital-acquired pathogen.

The MacArthur award is often called a “genius” grant.
Yeah, that’s ridiculous. They have this nice thing they sent me saying we don’t see this as a genius grant, it’s about creativity. If you ask my friends and family, they will say I’m no genius. I do not see myself as a genius. Mozart was a genius. But I do see myself as someone who has been creative in my path and has been enabled by really generous people who have worked with me on great opportunities. I find the genius rhetoric to not be really helpful. I think I’m old enough to appreciate that often these things say as much about the people who take the time to nominate you—and happen to be in the room, and their taste—as it does about you. Hopefully it says something about you, but it’s not entirely about you. I recognize there are many talented people who could be equally qualified for this recognition.

Your award monies come with no strings attached. What do you plan to do with your $625,000?
It still feels pretty surreal, and I haven’t decided. Fortunately we have several months to think about it before the money begins to come in increments. I would like to use the funds to promote science, including advancing the projects I care about. I’d also like to use it in the local community to help people recognize what a science career is like and how accessible it can be. Most people don’t realize if you go to grad school in science to get a PhD, it’s often covered by grants your advisor gets. I think that’s pretty great. I think it’s a fantastic thing about the sciences, and it makes it more accessible to people regardless of their background. It’s the closest thing we have to a meritocracy.

What drew you to your field originally?
I happened upon it completely serendipitously. I had enrolled in a graduate program in environmental engineering at MIT, and in my first semester I took an environmental microbiology class. I fell in love. I had never taken a class like that in college and it got me really excited because of the remarkable chemistry that biology catalyzes.

Your work is sometimes described as trying to combat antibiotic resistance.
Antibiotic resistance is an enormous problem. But when people use that language, usually what they are referring to is antibiotic resistance encoded by genes that are transferred horizontally by bacteria. I’m talking about something totally different here: I’m talking about a physiological form of resistance, which means that the bacteria are inherently more resistant to drugs, simply because the bugs are in a growth state where they don’t pick the drugs up—or if they pick them up, the drug’s target is no longer that relevant to their survival. I’m talking about chronic infections where an organism is growing slowly, like in the lungs of cystic fibrosis patients or in burn wound patients or in people with diabetic foot ulcers. Anytime you have infections that last for a long, long time where bacteria are hanging out for many years, that mode of growth allows them to persist—and that’s the type of physiological state that confers resistance to lots of drugs.

This week the U.N. General Assembly devoted a day to discussing antibiotic resistance. What do you see as the greatest challenge in this field?
Oh boy. I really have to think about that. It’s a hard question. Oof. [long pause] Well, I’m not sure if it’s the single greatest challenge but one of the biggest challenges at the basic science level is that the rate of microbial evolution can outpace our ability to rationally design new drugs—and I think that is very challenging inherently and scientifically. It’s a formidable challenge and that requires new ways of creatively thinking about the problem. The standard drug discovery pipelines we have had have clearly run into a wall, so it is an urgent problem.



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